Integrating analysis of proteome profile and drug screening identifies therapeutic potential of MET pathway for the treatment of malignant peripheral nerve sheath tumor.

BACKGROUND: Malignant peripheral nerve sheath tumor (MPNST) is an aggressive sarcoma with a poor prognosis that requires novel therapeutic agents. Proteome information is useful for identifying new therapeutic candidates because it directly reflects the biological phenotype. Additionally, in vitro drug screening is an effective tool to identify candidate drugs for common cancers. Hence, we attempted to identify novel therapeutic candidates for MPNST by integrating proteomic analysis and drug screening. METHODS: We performed comprehensive proteomic analysis on 23 MPNST tumor samples using liquid chromatography - tandem mass spectrometry to identify therapeutic targets. We also conducted drug screening of six MPNST cell lines using 214 drugs. RESULTS: Proteomic analysis revealed that the MET and IGF pathways were significantly enriched in the local recurrence/distant metastasis group of MPNST, whereas drug screening revealed that 24 drugs showed remarkable antitumor effects on the MPNST cell lines. By integrating the results of these two approaches, MET inhibitors, crizotinib and foretinib, were identified as novel therapeutic candidates for the treatment of MPNST. CONCLUSIONS: We successfully identified novel therapeutic candidates for the treatment of MPNST, namely crizotinib and foretinib, which target the MET pathway. We hope that these candidate drugs will contribute to the treatment of MPNST.

Metastatic chest wall malignant schwannoma responding to sorafenib: case report and literature review.

Malignant schwannomas or malignant peripheral nerve sheath tumors (MPNST) represent approximately 10% of all soft tissue sarcomas. Metastatic disease from chest wall MPNST is very rare. We present a case of a major clinical response to the tyrosine kinase inhibitor (TKI) sorafenib in a patient with metastatic MPNST. A 42-year-old female with a prior history of neurofibromas developed MPNST, which later metastasized to the lungs and brain. She was initially placed on sorafenib with significant clinical response to lung metastases. MPNST show high levels of Ras activity and hence these tumors are promising targets for TKIs. Studies are ongoing and the results are eagerly awaited regarding the responses to these medications and whether they can positively impact on the natural history of this disease.